The present invention relates to a marker for diagnosing an HER2 inhibitor-resistant cancer, a diagnostic kit including same, and a method for diagnosing an HER2 inhibitor-resistant cancer. More particularly, the present invention relates to a maker for diagnosing an HER2 inhibitor-resistant cancer, a diagnostic kit including same, and a method for diagnosing an HER2 inhibitor-resistant cancer, wherein the present invention allows presence and absence of resistance of an HER2-positive cancer patient against an HER2 inhibitor, which is typically prescribed to the HER2-positive cancer patient, to be determined in an easier way with remarkably high reliability.
Pharmaceutical industry continues to pursuit of therapeutic options for a novel drug which is more effective and more specific, or has little side effects than a drug administered nowadays. Due to genetic variance in the human population which causes a substantial difference in effects of many established drugs, an alternative of a drug therapy has been continuously developed. Therefore, although a wide range of drug therapy option is currently available, an additional therapy is required all times when a patient does not respond.
Typically, therapeutic paradigm used by a medical specialist is to prescribe a first-line drug resulted in the highest success rate as possible in disease treatment. When the first does not show an effect, an alternative drug therapy is successively prescribed. This paradigm is obviously not the best therapeutic method for certain diseases. For example, for a disease such as a cancer, commonly, a first treatment is the most important. Thus, there is an increased need to provide the best opportunity for successful treatment and to select a first drug which will be most effective for a disease of a particular patient. Cancer patients are no exception from the need. An approach through the most effective drug is required for cancer patients at the point of treatment.
HER family receptor tyrosine kinase is an important mediator of cell growth, differentiation, and survival. The receptor family includes four separate members including surface growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2 or p185neu), HER3 (ErbB3) and HER4 (ErbB4 or tyro2). Genes of the HER family have been reported to be involved in a malignant tumor of a human with a cause and effect relationship. Among them, P185neu, which relates to HER2, is firstly isolated from neuroblastoma of a chemically treated rat as a product of a transformed gene. It has been found that an activated form of neu proto-oncogene is derived from a point mutation (mutation into glutamic acid from valine) in a transmembrane region of a protein coded therein. It has been already reported in documents such as [Slamon et al., Science, 235:177-182 (1987)], [Slamon et al., Science, 244:707-712 (1989)] that amplification of human homologue of the neu is observed in breast cancer and ovarian cancer, and relates to poor prognosis. Further, it has been persistently reported that overexpression of the HER2 is observed in other types of cancers including cancers in stomach, endometrium, salivary gland, lung, kidney, colon, thyroid, pancreas, and bladder, indicating that HER2 relates to the cancer above.
According to data reported so far, it has been known that about 15 to 20% of whole breast cancers have HER2 protein overexpression on cell surfaces thereof, and such tumors exhibit poorer prognosis than case where HER2 overexpression is not exhibited.
Thus, a number of drugs targeting to HER2 signaling typically have been developed as a tool of stopping growth of cancer cells showing HER2 protein overexpression. Herceptin (Trastuzumab), which is developed by Genentech, is one of these drugs. It has been demonstrated that herceptin is effective in prolong of survival of a patient who is diagnosed as advanced breast cancer showing HER2 overexpression. Also, it has been reported that herceptin reduces recurrence and death of a patient with early phase breast cancer having HER2 protein overexpression or HER2 gene amplification.
Consequently, when diagnosed as HER2-positive cancer, particularly, breast cancer, herceptin is typically prescribed. However, after prescription, a case appears in which cancer recurs or cancer metastasis occurs in a patient fully recovered from breast cancer after a certain period of time. It has been demonstrated that an occurrence of a mechanism of acquiring herceptin resistance is a cause of such case. As an example of the demonstration above, it has been found that, in transformed mice, new tumors are generated in most of mice within 1 to 9 months after HER2/neu transgene expression has been stopped; and the tumors are obviously variants of the tumors which are initially generated, and irrelevant to HER2/neu over expression, wherein the transformed mice are programmed such that mammary gland tumors are generated in a determined time by HER2/neu mutation, which is an oncogene, and then stopped.
Consequently, unstable genomes of cancer cells produce new alleles thereby having new properties which make proliferation ability to be enhanced. Then, the number of cells acquiring the genetic/epigenetic change is expanded to thereby induce cancer recurrence. Thus, after initially achieving success in reduction of tumor cell number, new types of cancer cells having resistance thereto are proliferated. Therefore, it is very important to determine presence and absence of resistance to the prescribed drug for cancer therapy.
However, a biomarker or diagnostic kit for determining whether a cancer patient has resistance to an HER2 inhibitor prescribed to an HER2-positive cancer patient (such as herceptin) are stilled during research and development so that there is no commercially available product. Also, a prototype product has a limitation in that high reliability is not achieved. Due to the current circumstance as above, in most cases, a costly drug such as lapatinib is inevitably prescribed to a HER2-positive cancer patient typically combined with herceptin. However, the combination therapy is not patient-customized therapy, but prescription including all number of cases which causes a problem of overtreatment. Further, the overtreatment has critical limitation, that is, incidence of side effects in a patient caused by prescription of an unnecessary drug and increased medical expenses.
Thus, it is urgently required to develop a biomarker, and diagnostic kit capable of easily determining whether a cancer patient has resistance to an HER2 inhibitor with high reliability.